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1.
J Physiol ; 602(8): 1815-1833, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38381008

RESUMEN

Renin is the key enzyme of the systemic renin-angiotensin-aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin-1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero-Cre (P0-Cre) to abrogate Nrp1 constitutively in P0-Cre lineage-labelled cells of the kidney. We found that the P0-Cre precursor cells differentiate into renin-producing JG cells. We employed a lineage-tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell-autonomous role for NRP1 in JG cell function. Nrp1-deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0-Cre-expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. KEY POINTS: Renin is a centrepiece of the renin-angiotensin-aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney. Neuropilin-1 (NRP1) is a conserved membrane-bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression. We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function. Cell-specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance. The results support the versatility of renin-producing cells in the kidney and may open new avenues for therapeutic approaches.


Asunto(s)
Aparato Yuxtaglomerular , Renina , Ratones , Animales , Renina/metabolismo , Aparato Yuxtaglomerular/metabolismo , Neuropilina-1/genética , Neuropilina-1/metabolismo , Riñón/metabolismo , Ratones Noqueados , Sodio/metabolismo
2.
Rheumatology (Oxford) ; 62(12): 3978-3983, 2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-37021930

RESUMEN

OBJECTIVES: To investigate whether the lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. METHODS: We used whole-exome sequencing for two families and a targeted gene-sequencing panel for an isolated patient. d-lactate dosages were analysed using ELISA. RESULTS: We demonstrated linkage of juvenile-onset gout to homozygous carriage of three rare distinct LDHD variants in three different ethnicities. In a Melanesian family, the variant was (NM_153486.3: c.206C>T; rs1035398551) and, as compared with non-homozygotes, homozygotes had higher hyperuricaemia (P = 0.02), lower fractional clearance of urate (P = 0.002), and higher levels of d-lactate in blood (P = 0.04) and urine (P = 0.06). In a second, Vietnamese, family, very severe juvenile-onset gout was linked to homozygote carriage of an undescribed LDHD variant (NM_153486.3: c.1363dupG) leading to a frameshift followed by a stop codon, p.(AlaGly432fsTer58). Finally, a Moroccan man, with early-onset and high d-lactaturia, whose family was unavailable for testing, was homozygous for another rare LDHD variant [NM_153486.3: c.752C>T, p.(Thr251Met)]. CONCLUSION: Rare, damaging LDHD variants can cause autosomal recessive early-onset gout, the diagnosis of which can be suspected by measuring high d-lactate levels in the blood and/or urine.


Asunto(s)
Gota , Hiperuricemia , Masculino , Humanos , Gota/genética , Hiperuricemia/genética , Homocigoto , Ácido Láctico , Lactato Deshidrogenasas/genética
4.
Am J Nephrol ; 53(1): 59-68, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35038711

RESUMEN

INTRODUCTION: Renal involvement is a severe manifestation of antineutrophil cytoplasmic antibody-associated vasculitis. Patients often progress to end-stage renal disease. The potential for renal recovery after the first flare has seldom been studied. Our objectives were to describe the evolution of the estimated glomerular filtration rate (eGFR) and identify factors associated with the change in the eGFR between diagnosis and the follow-up at 3 months (ΔeGFRM0-M3). METHODS: This was a retrospective study over the period 2003-2018 of incident patients in the Nord-Pas-de-Calais (France). The primary outcome was the ΔeGFRM0-M3. RESULTS: One hundred and seventy-seven patients were included. The eGFR at 3 months was significantly higher than at diagnosis (mean ± standard deviation, 40 ± 24 vs. 28 ± 26 mL/min/1.73 m2, p < 0.001), with a ΔeGFRM0-M3 of 12 ± 19 mL/min/1.73 m2. The eGFR at 12 months was higher than at 3 months (44 ± 13 vs. 40 ± 24 mL/min/1.73 m2, p = 0.003). The factors significantly associated with the ΔeGFRM0-M3 in multivariate analysis were the percentage of cellular crescents and neurological involvement. The mean increase in the eGFR was 2.90 ± 0.06 mL/min/1.73 m2 for every 10-point gain in the percentage of cellular crescents. CONCLUSIONS: Early renal recovery after the first flare of pauci-immune glomerulonephritis occurred mainly in the first 3 months of treatment. The percentage of cellular crescents was the main independent predictor of early renal recovery.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis , Anticuerpos Anticitoplasma de Neutrófilos , Femenino , Glomerulonefritis/diagnóstico , Humanos , Riñón , Masculino , Estudios Retrospectivos
5.
Int J Mol Sci ; 23(4)2022 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-35216422

RESUMEN

Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by ABCC6 mutations, inducing a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in arteries. METHODS: we analyzed whether long-term exposure of Abcc6-/- mice (a murine model of PXE) to a mild vitamin D supplementation, with or without calcium, would impact the development of vascular calcification. Eight groups of mice (including Abcc6-/- and wild-type) received vitamin D supplementation every 2 weeks, a calcium-enriched diet alone (calcium in drinking water), both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Aorta and kidney artery calcification was assessed by 3D-micro-computed tomography, Optical PhotoThermal IR (OPTIR) spectroscopy, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and Yasue staining. RESULTS: at 6 months, although vitamin D and/or calcium did not significantly increase serum calcium levels, vitamin D and calcium supplementation significantly worsened aorta and renal artery calcification in Abcc6-/- mice. CONCLUSIONS: vitamin D and/or calcium supplementation accelerate vascular calcification in a murine model of PXE. These results sound a warning regarding the use of these supplementations in PXE patients and, to a larger extent, patients with low systemic pyrophosphate levels.


Asunto(s)
Calcificación Fisiológica/efectos de los fármacos , Calcio de la Dieta/farmacología , Calcio/farmacología , Seudoxantoma Elástico/tratamiento farmacológico , Calcificación Vascular/tratamiento farmacológico , Vitamina D/farmacología , Animales , Arterias/efectos de los fármacos , Arterias/metabolismo , Suplementos Dietéticos , Modelos Animales de Enfermedad , Femenino , Ratones , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Seudoxantoma Elástico/metabolismo , Calcificación Vascular/metabolismo
6.
J Cell Mol Med ; 24(20): 11791-11799, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32885586

RESUMEN

Trauma-induced calcification is the pathological consequence of complex injuries which often affect the central nervous system and other parts of the body simultaneously. We demonstrated by an animal model recapitulating the calcification of the above condition that adrenaline transmits the stress signal of brain injury to the calcifying tissues. We have also found that although the level of plasma pyrophosphate, the endogenous inhibitor of calcification, was normal in calcifying animals, it could not counteract the acute calcification. However, externally added pyrophosphate inhibited calcification even when it was administered after the complex injuries. Our finding suggests a potentially powerful clinical intervention of calcification triggered by polytrauma injuries which has no effective treatment.


Asunto(s)
Lesiones Traumáticas del Encéfalo/complicaciones , Difosfatos/uso terapéutico , Osificación Heterotópica/complicaciones , Calcificación Vascular/etiología , Antagonistas Adrenérgicos/farmacología , Animales , Lesiones Traumáticas del Encéfalo/patología , Cardiotoxinas , Difosfatos/sangre , Modelos Animales de Enfermedad , Epinefrina , Femenino , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Osificación Heterotópica/sangre , Osificación Heterotópica/diagnóstico por imagen , Receptores Adrenérgicos/metabolismo , Calcificación Vascular/sangre , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/genética , Microtomografía por Rayos X
7.
Int J Mol Sci ; 20(24)2019 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-31861118

RESUMEN

Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall's plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease.


Asunto(s)
Difosfatos/metabolismo , Cálculos Renales/metabolismo , Seudoxantoma Elástico/metabolismo , Enfermedades Raras/metabolismo , Urolitiasis/metabolismo , Calcificación Vascular/metabolismo , 5'-Nucleotidasa/genética , Proteínas Ligadas a GPI/genética , Humanos , Cálculos Renales/complicaciones , Cálculos Renales/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Mutación , Seudoxantoma Elástico/complicaciones , Seudoxantoma Elástico/genética , Enfermedades Raras/complicaciones , Enfermedades Raras/genética , Urolitiasis/complicaciones , Urolitiasis/genética , Calcificación Vascular/complicaciones , Calcificación Vascular/genética
10.
J Mol Med (Berl) ; 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39136767

RESUMEN

One of the hallmarks of chronic kidney disease (CKD) is the development of vascular calcification. Inorganic pyrophosphate is a potent inhibitor of calcification, and previous studies have reported low plasma pyrophosphate levels in hemodialysis patients. A long-term mouse model of CKD-accelerated vascular calcification was developed to study pyrophosphate metabolism and to test whether oral pyrophosphate supplementation attenuates the propensity for arterial calcification. CKD was induced by repeated injections of aristolochic acid in wild-type and Abcc6-/- mice, which tend to develop vascular calcifications. CKD accelerated the development of vascular calcifications in Abcc6-/- mice, in the aorta and small renal arteries, and decreased circulating pyrophosphate levels. Oral pyrophosphate supplementation for 6 months attenuated CKD-induced vascular calcification in this model. These results show that oral pyrophosphate may be of interest in preventing vascular calcification in patients with CKD. KEY MESSAGES: Chronic kidney disease accelerates the development of vascular calcification in pyrophosphate-deficient mice. Oral pyrophosphate supplementation for 6 months attenuates chronic kidney disease-induced vascular calcification in a mouse model. Oral pyrophosphate may be of interest in preventing vascular calcification in patients with chronic kidney disease.

11.
Nephrol Ther ; 14(2): 112-116, 2018 Apr.
Artículo en Francés | MEDLINE | ID: mdl-29295766

RESUMEN

We report a case of a 43 years old man who was intoxicated by a 25g vancomycin overload. An anuric acute renal failure rapidly occured. The vancomycinemia was measured as high as 360mg/L (normal range: 15-35mg/L). We started an intermittent hemodialysis program to clear out the vancomycin. The vancomycinemia decreased below the treshold of our laboratory after the eighth session. Three supplementary sessions were needed because of a persistant oliguria. The kidney function slowly improved and was back to normal (seric creatinin: 80micromol/L) 3 weeks after the patient had gone home. To our knowledge, it is the first success of this technic concerning vancomycin poisoning in adults with anuric kidney failure.


Asunto(s)
Lesión Renal Aguda/inducido químicamente , Antibacterianos/envenenamiento , Diálisis Renal/métodos , Vancomicina/envenenamiento , Lesión Renal Aguda/terapia , Adulto , Antibacterianos/sangre , Humanos , Masculino , Vancomicina/sangre
12.
J Intensive Care ; 5: 70, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29276608

RESUMEN

BACKGROUND: Lithium poisoning could trigger multiple complications. We report the case of a lithium poisoning with five complications that are described for the first time together. CASE REPORT: A 60-year-old woman was admitted in our intensive care unit for altered consciousness. Severe lithium intoxication was diagnosed (lithium plasmatic level 8.21 mmol/l) associated with acute oliguric kidney failure. Continuous renal replacement therapy was started immediately. Orotracheal intubation was quickly required because of status epilepticus. Medullary aplasia happened 48 h after the patient was intubated. Infectious and immunological causes were ruled out and lithium poisoning was considered as the most likely etiology. Iterative blood and platelet transfusion were required. Severe polyneuropathy was diagnosed on the 5th day after admission. The patient showed a peripheral tetraparesia and cranial nerve failure while lithium plasmatic level had decreased to a therapeutic level. Conversely, urine output increased and hypernatremia promptly occurred, which led to diabetes insipidus diagnosis. Neuropathy decreased in 72 h and the patient was definitely extubated by the 11th day. Hematologic disturbances decreased and no blood transfusion would be required after the 8th day. The patient would keep sequellas of the poisoning. Thin motricity would still be altered and polyuria would remain. Diffuse alopecia was promptly observed, with no iron deficiency or thyroid disturbance. CONCLUSION: In addition to presenting this case report, we herein discuss the drug causality, the consequences, and the plausible pathophysiology of these five situations.

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